Analysis of alpha-synuclein amyloid fibrils and their effects on the cellular proteome

Misfolded α-synuclein aggregates into amyloid fibrils. These fibrils are the principal component of Lewy Bodies, intracellular inclusions that are one of the pathological hallmarks of Parkinson’s disease. Despite the accumulation of α-synuclein fibrils being a marker for disease, their contribution to Lewy Body pathology and disease progression is not well understood. Exogenous α-synuclein fibrils are able to seed the formation of Lewy Bodies by promoting the aggregation of endogenous α-synuclein. Using proteomics, this project aimed to determine how the presence of α-synuclein fibrils affected the cellular proteome in the early stages of Lewy Body formation using SH-SY5Y cells that overexpress GFP-α-synuclein as a model. Tandem mass tagging quantitative proteomics identified 11 proteins with significantly altered levels resulting from exposure of the SH-SY5Y GFP-α-synuclein cell line to α-synuclein fibrils for 1 and 5 days. Among these proteins were members of the collagen and microtubule-associated protein families, they have roles in a plethora of cellular processes including signalling, structural maintenance and intracellular organisation. Alterations to their function could cause cellular dysfunction, which could contribute to the pathogenic conditions seen in Lewy Body formation and Parkinson’s disease. This highlights the importance of proteomics in further understanding the contribution that α-synuclein has in the pathology and progression of Parkinson’s disease and other related diseases.